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Generation of an induced pluripotent stem cell line (TRNDi004-I) from a Niemann-Pick disease type B patient carrying a heterozygous mutation of p.L43_A44delLA in the SMPD1 gene.

ABSTRACT: Niemann-Pick disease type B (NPB) is a rare autosomal recessive lysosomal storage disease caused by mutations in the SMPD1 gene, which encodes for acid sphingomyelinase. A human induced pluripotent stem cell (iPSC) line was generated from dermal fibroblasts of a 1-year old male patient with NPB that has a heterozygous mutation of a p.L43_A44delLA of SMPD1 using non-integrating Sendai virus technique. This iPSC line offers a useful resource to study the disease pathophysiology and as a cell-based model for drug development to treat NPB.

SUBMITTER: Baskfield A

PROVIDER: S-EPMC6643268 | biostudies-literature |

REPOSITORIES: biostudies-literature

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An induced pluripotent stem cell line (TRNDi009-C) from a Niemann-Pick disease type A patient carrying a heterozygous p.L302P (c.905 T>C) mutation in the SMPD1 gene.

Project description:Niemann-Pick disease type A (NPA) is a rare autosomal recessive lysosomal storage disease caused by mutations in the SMPD1 gene, which encodes for the protein acid sphingomyelinase. A human induced pluripotent stem cell (iPSC) line was generated from dermal fibroblasts of a 21-fetal-week-old female patient with NPA that has a heterozygous mutation of a p.L302P variant (c.905 T > C) using non-integrating Sendai virus technique. This iPSC line offers a useful resource to study the disease pathophysiology and as a cell-based model for drug development to treat NPA.

| S-EPMC6686851 | biostudies-literature

Characterization of common SMPD1 mutations causing types A and B Niemann-Pick disease and generation of mutation-specific mouse models.

Project description:Herein we describe detailed characterization of four common mutations (L302P, H421Y, R496L and DeltaR608) within the acid sphingomyelinase (ASM) gene causing types A and B Niemann-Pick disease (NPD). In vitro and in situ enzyme assays revealed marked deficiencies of ASM activity in NPD cell lines homoallelic for each mutation, although Western blotting and fluorescent microscopy showed that the mutant ASM polypeptides were expressed at normal levels and trafficked to lysosomes. Co-immunoprecipitation of the polypeptides with the ER chaperone, BiP, confirmed these findings, as did in vitro expression of the mutant cDNAs in reticulocyte lysates. We further developed a computer assisted, three-dimensional model of human ASM based on homologies to known proteins, and used this model to map each NPD mutation in relation to putative substrate binding, hydrolysis and zinc-binding domains. Lastly, we generated transgenic mice expressing the R496L and DeltaR608 mutations on the complete ASM knock-out background (ASMKO), and established breeding colonies for the future evaluation of enzyme enhancement therapies. Analysis of these mice demonstrated that the mutant ASM transgenes were expressed at high levels in the brain, and in the case of the DeltaR608 mutation, produced residual ASM activity that was significantly above the ASMKO background.

| S-EPMC2621017 | biostudies-literature

Deep sequencing of SMPD1 gene revealed a heterozygous frameshift mutation (p.Ser192Alafs) in a Palestinian infant with Niemann-Pick disease type A: a case report.

Project description:BackgroundNiemann-Pick disease is caused by reduced level of the lysosomal enzyme acid sphingomyelinase. Children can survive between 2 and 12 years based on the disease type. Two main types are well known: type A and B. Niemann-Pick disease type A is characterized by severe central nervous system deterioration and hepatosplenomegaly while type B is a progressive hypersplenism accompanied with gradual deterioration of pulmonary function.Case presentationWe describe an 11-month-old Palestinian baby boy with hepatosplenomegaly, hypotonia, delayed motor development, laryngomalacia, bilateral cherry-red spots, and failure to thrive. Metabolic screening, blood count, differential tests, immunology screen, infectious disease screen, urine, biochemical tests as well as molecular diagnosis were performed. The molecular diagnosis was done by amplifying the whole sphingomyelin phosphodiesterase 1 (SMPD1) gene, followed by deep sequencing. The obtained sequences were aligned, de novo assembled and compared to human reference gene (GenBank GeneID: NG_011780.1, Ensembl version ENSG00000166311 and protein identified as UniProtKB - P17405). Two known mutations were identified in our patient: the pathogenic frameshift mutation NM_000543.4(SMPD1):c.573delT (p.Ser192Alafs) and the benign polymorphism NM_000543.4(SMPD1):c.107T>C (p.Val36Ala). The enzyme study showed a very low level of enzymatic activity of acidic sphingomyelinase (0.1 nmol/ml per hour). Correlations between clinical findings, laboratory data, and sequence analysis are presented.ConclusionsIn conclusion, this is the first report about a heterozygote frameshift p.Ser192AlafsX65 in a Palestinian patient with Niemann-Pick disease type A, emphasizing the importance of deep sequencing in genetic diagnosis of this rare inherited disease.

| S-EPMC6142321 | biostudies-literature

An induced pluripotent stem cell line (TRNDi001-D) from a Niemann-Pick disease type C1 (NPC1) patient carrying a homozygous p. I1061T (c. 3182T>C) mutation in the NPC1 gene.

Project description:Niemann-Pick disease, type C (NPC) is a rare autosomal recessive genetic disease caused by mutations in either NPC1 or NPC2, which encodes an intracellular cholesterol-binding protein in lysosome. Deficiency of either NPC1 or NPC2 protein results in malfunction of intracellular cholesterol trafficking and lysosomal accumulation of unesterified cholesterols. A human induced pluripotent stem cell (iPSC) line was generated from dermal fibroblasts of a male patient that has a homozygous p.I1061T missense mutation in NPC1 using a non-integrating Sendai virus technique. This NPC1 iPSC line offers a useful resource for disease modeling and drug development.

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Generation of an Alagille syndrome (ALGS) patient-derived induced pluripotent stem cell line (TRNDi032-A) carrying a heterozygous mutation (p.Cys682Leufs*7) in the JAG1 gene.

Project description:Alagille syndrome (ALGS) is an autosomal dominant, multisystemic disorder due to haploinsufficiency in either the JAG1 gene (ALGS type 1) or the NOTCH2 gene (ALGS type 2). The disease has been difficult to diagnose and treat due to its muti-system clinical presentation, variable expressivity, and prenatal onset for some of the features. The generation of this iPSC line (TRNDi032-A) carrying a heterozygous mutation, p.Cys682Leufs*7 (c.2044dup), in the JAG1 gene provides a means of studying the disease and developing novel therapeutics towards patient treatment.

| S-EPMC10842201 | biostudies-literature

Characterization of Niemann-Pick diseases genes mutation spectrum in Iran and identification of a novel mutation in SMPD1 gene.

Project description:Background: Niemann-Pick diseases are rare inherited lipid storage disorders caused by mutations in the SMPD1, NPC1, and NPC2 genes. The aim of this study was to assess the mutation spectrum of a cohort of Iranian Niemann-Pick patients. Methods: A consanguineous couple with a child suspected of having Niemann-Pick disease type A (died at age 2) was screened for gene mutations in the SMPD1 gene. Sanger sequencing was performed for all exons and exon-intron boundary regions. A literature review on SMPD1, NPC1, and NPC2 genes mutations in Iran was conducted using published original papers on this subject. Results: A novel frameshift c.762delG (p.Leu256fs*) at a heterozygous state was identified in the parents. According to the review study, identified mutations in 39 Iranian patients were concentrated in exon 2 of the SMPD1 gene and exons 8 and 9 of the NPC1 gene. Conclusion: Niemann-Pick diseases genes mutation analysis (SMPD1, NPC1, and NPC2) in Iran shows the genetic heterogeneity of these diseases in this country. More studies with larger sample sizes should be conducted to further examine genetic changes associated with Niemann-Pick diseases in Iran.

| S-EPMC7137857 | biostudies-literature

Mutational spectrum of SMPD1 gene in Pakistani Niemann-Pick disease patients.

Project description:Objective:Genetic variation analysis of rare autosomal recessive Niemann-Pick disease (NPD) Pakistani patients. Methods:We sequenced the SMPD1 gene including its all coding and flanking regions in seven unrelated sporadic patients suffering from Niemann-Pick disease through targeted exome sequencing. Genetic variants mapping and their protein predictions were evaluated using different bioinformatics tools and clinical phenotypes were correlated. The study was conducted from January 2018 to March 2019 at The Children's Hospital Lahore. Results:We have mapped five different mutations in SMPD1 gene of enrolled patients with a novel homozygous missense variant (c.1718G>C) (p.Trp573Ser) in one patient. A missense mutation (c.1267C>T) (p.His423Tyr) has been identified in three unrelated patients. A nonsense mutation (c.1327C>T) (p.Arg443Term) and one missense mutation (c.1493G>A) (p.Arg498His) mapped in one patient each. A compound heterozygous mutation has been mapped in one patient (c.740G>A) (p.Gly247Asp); (c.1493G>A) (p.Arg498His). Pathogenic effect of novel variant has been predicted through in-silico analysis and has not been reported in general overall population in the globe. Conclusion:This is the first report of genetic demographic assessment of Niemann-Pick disease in Pakistan. The mapped mutations would be helpful to build a disease variants algorithm of Pakistani population. This will be used for determining disease clinical magnitude along with provision of genetic screening services in affected families.

| S-EPMC7150380 | biostudies-literature

Generation of human induced pluripotent stem cell lines carrying heterozygous PLN mutation from dilated cardiomyopathy patients.

Project description:Familial dilated cardiomyopathy (DCM) is among the most prevalent forms of inherited heart disease. Here, two human-induced pluripotent stem cell (iPSC) lines were generated from peripheral blood mononuclear cells (PBMCs) from DCM patients carrying different mutations in the phospholamban encoding-gene (PLN). Both iPSC lines exhibited normal morphology, karyotype, pluripotency marker expression, and differentiation into the three germ layers. These patient-specific iPSC lines serve as valuable in vitro models for DCM pathology caused by PLN mutations.

| S-EPMC9681708 | biostudies-literature

Imprinting at the SMPD1 locus: implications for acid sphingomyelinase-deficient Niemann-Pick disease.

Project description:Acid sphingomyelinase (ASM) is the lipid hydrolase that is deficient in types A and B Niemann-Pick disease (NPD). Here, we demonstrate that the gene encoding ASM (SMPD1) is paternally imprinted and that differential expression of the mutant alleles in patients with ASM-deficient NPD and in carriers influences the disease phenotype. Comparison of the results of genomic sequencing versus reverse-transcriptase polymerase chain reaction sequencing for several patients with NPD revealed preferential expression of one mutant allele. Further analysis of one family showed that the expressed allele was maternally inherited and that the distinct clinical presentations of the individual patients were correlated with the amount of residual ASM activity expressed from the maternal mutation. Treatment of NPD cell lines with 5-aza-2'-deoxycytidine enhanced the expression of the paternal SMPD1 allele, and bisulfite genomic sequencing identified which CpG dinucleotides within the SMPD1 promoter were methylated. In a related set of studies, we identified a carrier individual who had approximately 15% of normal ASM activity and clinical features of ASM-deficient NPD. DNA sequencing confirmed that this individual carried a single SMPD1 mutation and that this mutant allele was preferentially expressed. These data thus demonstrate, for the first time, imprinting at the SMPD1 gene and reveal the influence of this epigenetic modification on the presentation of ASM-deficient NPD.

| S-EPMC1474038 | biostudies-literature

Alleged Detrimental Mutations in the SMPD1 Gene in Patients with Niemann-Pick Disease.

Project description:Loss-of-function mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene are associated with decreased catalytic activity of acid sphingomyelinase (ASM) and are the cause of the autosomal recessive lysosomal storage disorder Niemann-Pick disease (NPD) types A and B. Currently, >100 missense mutations in SMPD1 are listed in the Human Gene Mutation Database. However, not every sequence variation in SMPD1 is detrimental and gives rise to NPD. We have analysed several alleged SMPD1 missense mutations mentioned in a recent publication and found them to be common variants of SMPD1 that give rise to normal in vivo and in vitro ASM activity. (Comment on Manshadi et al. Int. J. Mol. Sci. 2015, 16, 6668-6676).

| S-EPMC4490514 | biostudies-literature

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